For more than 25 years, the research program supported by this grant has focused on the hypothesis that insulin functions as an "adiposity negative feedback signal" that circulates at concentrations proportionate to body fat mass, enters the brain, and acts upon discrete neuronal systems that control food intake and autonomic function. The net effect of this central action is 'catabolic' in nature, promoting reductions of food intake and body weight via actions in the hypothalamic arcuate nucleus (ARC). Following the cloning of the ob gene, this model was expanded to include the adipocyte hormone, leptin. It has subsequently become evident that many of leptin's CNS effects overlap with those induced by insulin, and our data indicate that the anorexic effects of both hormones requires signaling via a single intracellular pathway -- the insulin receptor substrate-phosphotidylinositol 3-OH kinase (IRS-PI3K) pathway -- in hypothalamic neurons. One way in which insulin and leptin may reduce food intake is by hastening the onset of satiety, a biological state that is elicited by neurohumoral stimuli including cholecystokinin (CCK) that act in hindbrain areas such as the nucleus tractus solitarius (NTS). To explain this interaction, we propose that a descending projection from the hypothalamus links the response to adiposity-related signals to hindbrain circuits that respond to satiety signals. The first Specific Aim of this proposal is to determine if actions of insulin and leptin in the ARC regulate the hindbrain response to CCK via a mechanism that requires PI3K signaling. An exciting new area of study revolves around the hypothesis that acute neuronal effects of insulin and leptin converge upon those induced by intracellular long-chain fatty-acyl CoA (LCFAcoA) molecules. Specific Aims 2-4 will determine if hypothalamic LCFAcoA content is regulated by acute changes of energy balance, and whether insulin and leptin exert effects on hypothalamic neurons that are dependent on FACoA signaling. Specific: Aim 5 investigates whether hypothalamic FACoA signaling, like that of insulin or leptin, potentiates the hindbrain response to satiety signals. Together, these aims constitute a body of work with the potential to revise our understanding of energy homeostasis and obesity pathogenesis, and will provide important new direction to ongoing efforts to develop more successful approaches to obesity treatment.